Rapid-onset dystonia-parkinsonism (RDP, DYT12) is an autosomal-dominant disorder characterized by sudden onset of dystonia and parkinsonism. The symptoms of RDP include limb and cranial dystonic spasms, bradykinesia, slow gait, dysarthria, dysphagia, and postural instability. It has recently been demonstrated that RDP is associated with loss of function mutations in the alpha-3 isoform of the Na/K- ATPase (sodium) pump. Despite understanding the genetic and molecular substrate of RDP, there are currently no specific hypotheses as to how these mutations cause dystonia or parkinsonism. Dysfunction of the dopaminergic neurons of the basal ganglia is the most common cause of dystonia. Patients suffering from RDP are not responsive to L-dopa treatment, and there is no evidence for involvement of the dopaminergic system. In order to be successful in providing rational and effective therapy, it is clearly necessary to elucidate the site and the nature of this disorder. This exploratory R21 grant proposal presents arguments in support of, and experiments to test, the hypothesis that RDP is caused by the malfunction of cerebellar Purkinje cells. This is based on the fact that abnormal cerebellar signaling causes dystonia and many of the symptoms seen in RDP patients are those associated with cerebellar dysfunction. We will test two specific hypotheses. In the first we will explore whether dysfunction of cerebellar sodium pumps can cause dystonia. This will be achieved by chronic in vivo perfusion of selective sodium pump blockers into the cerebellum of rats. Similar experiments will explore the potential involvement of the basal ganglia, the thalamus, and motor cortex. In the second specific aim we will test the hypothesis that cerebellar Purkinje cells are exquisitely sensitive to dysfunction of the sodium pumps. Completion of the experiments proposed in this exploratory grant may potentially identify the cerebellum as the site and cause of dysfunction in rapid-onset dystonia-Parkinsonism, and may thus challenge the dogma that only dysfunction of the basal ganglia causes dystonia. [unreadable] [unreadable] [unreadable]